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  1. Article ; Online: Asymptomatic recrudescence after artemether–lumefantrine treatment for uncomplicated falciparum malaria

    Rida Mumtaz / Lucy C. Okell / Joseph D. Challenger

    Malaria Journal, Vol 19, Iss 1, Pp 1-

    a systematic review and meta-analysis

    2020  Volume 9

    Abstract: Abstract Background In clinical trials of therapy for uncomplicated Plasmodium falciparum, there are usually some patients who fail treatment even in the absence of drug resistance. Treatment failures, which can be due to recrudescence or re-infection, ... ...

    Abstract Abstract Background In clinical trials of therapy for uncomplicated Plasmodium falciparum, there are usually some patients who fail treatment even in the absence of drug resistance. Treatment failures, which can be due to recrudescence or re-infection, are categorized as ‘clinical’ or ‘parasitological’ failures, the former indicating that symptoms have returned. Asymptomatic recrudescence has public health implications for continued malaria transmission and may be important for the spread of drug-resistant malaria. As the number of recrudescences in an individual trial is often low, it is difficult to assess how commonplace asymptomatic recrudescence is, and with what factors it is associated. Methods A systematic literature review was carried out on clinical trials of artemether-lumefantrine (AL) in patients seeking treatment for symptomatic uncomplicated falciparum malaria, and information on symptoms during treatment failure was recorded. Only treatment failures examined by polymerase chain reaction (PCR) were included, so as to exclude re-infections. A multivariable Bayesian regression model was used to explore factors potentially explaining the proportion of recrudescent infections which are symptomatic across the trials included in the study. Results Across 60 published trials, including 9137 malaria patients, 37.8% [95% CIs (26.6–49.4%)] of recrudescences were symptomatic. A positive association was found between transmission intensity and the observed proportion of recrudescences that were asymptomatic. Symptoms were more likely to return in trials that only enrolled children aged < 72 months [odds ratio = 1.62, 95% CIs (1.01, 2.59)]. However, 84 studies had to be excluded from this analysis, as recrudescences were not specified as symptomatic or asymptomatic. Conclusions AL, the most widely used treatment for uncomplicated P. falciparum in Africa, remains a highly efficacious drug in most endemic countries. However in the small proportion of patients where AL does not clear parasitaemia, the majority of patients do not develop symptoms again and thus would be unlikely to seek another course of treatment. This continued asymptomatic parasite carriage in patients who have been treated may have implications for drug-resistant parasites being introduced into high-transmissions settings.
    Keywords Malaria ; Plasmodium falciparum ; Artemisinin-based combination therapy ; Artemether–lumefantrine ; Clinical trials ; Treatment failure ; Arctic medicine. Tropical medicine ; RC955-962 ; Infectious and parasitic diseases ; RC109-216
    Subject code 610
    Language English
    Publishing date 2020-12-01T00:00:00Z
    Publisher BMC
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  2. Article ; Online: Mapping sulphadoxine-pyrimethamine-resistant Plasmodium falciparum malaria in infected humans and in parasite populations in Africa

    Lucy C. Okell / Jamie T. Griffin / Cally Roper

    Scientific Reports, Vol 7, Iss 1, Pp 1-

    2017  Volume 15

    Abstract: Abstract Intermittent preventive treatment (IPT) with sulphadoxine-pyrimethamine in vulnerable populations reduces malaria morbidity in Africa, but resistance mutations in the parasite dhps gene (combined with dhfr mutations) threaten its efficacy. We ... ...

    Abstract Abstract Intermittent preventive treatment (IPT) with sulphadoxine-pyrimethamine in vulnerable populations reduces malaria morbidity in Africa, but resistance mutations in the parasite dhps gene (combined with dhfr mutations) threaten its efficacy. We update a systematic review to map the prevalence of K540E and A581G mutations in 294 surveys of infected humans across Africa from 2004-present. Interpreting these data is complicated by multiclonal infections in humans, especially in high transmission areas. We extend statistical methods to estimate the frequency, i.e. the proportion of resistant clones in the parasite population at each location, and so standardise for varying transmission levels. Both K540E and A581G mutations increased in prevalence and frequency in 60% of areas after 2008, highlighting the need for ongoing surveillance. Resistance measures within countries were similar within 300 km, suggesting an appropriate spatial scale for surveillance. Spread of the mutations tended to accelerate once their prevalence exceeded 10% (prior to fixation). Frequencies of resistance in parasite populations are the same or lower than prevalence in humans, so more areas would be classified as likely to benefit from IPT if similar frequency thresholds were applied. We propose that the use of resistance frequencies as well as prevalence measures for policy decisions should be evaluated.
    Keywords Medicine ; R ; Science ; Q
    Language English
    Publishing date 2017-08-01T00:00:00Z
    Publisher Nature Portfolio
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  3. Article ; Online: Impact of seasonal malaria chemoprevention on prevalence of malaria infection in malaria indicator surveys in Burkina Faso and Nigeria

    Lucy C Okell / Patrick Walker / Olusola Oresanya / Sol Richardson / Monica Anna de Cola / Benoît Sawadogo / Taiwo Ibinaiye / Adama Traoré / Cheick Saïd Compaoré / Chibuzo Oguoma / Gauthier Tougri / Christian Rassi / Arantxa Roca-Feltrer

    BMJ Global Health, Vol 7, Iss

    2022  Volume 5

    Keywords Medicine (General) ; R5-920 ; Infectious and parasitic diseases ; RC109-216
    Language English
    Publishing date 2022-05-01T00:00:00Z
    Publisher BMJ Publishing Group
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  4. Article ; Online: Modelling upper respiratory viral load dynamics of SARS-CoV-2

    Joseph D. Challenger / Cher Y. Foo / Yue Wu / Ada W. C. Yan / Mahdi Moradi Marjaneh / Felicity Liew / Ryan S. Thwaites / Lucy C. Okell / Aubrey J. Cunnington

    BMC Medicine, Vol 20, Iss 1, Pp 1-

    2022  Volume 20

    Abstract: Abstract Relationships between viral load, severity of illness, and transmissibility of virus are fundamental to understanding pathogenesis and devising better therapeutic and prevention strategies for COVID-19. Here we present within-host modelling of ... ...

    Abstract Abstract Relationships between viral load, severity of illness, and transmissibility of virus are fundamental to understanding pathogenesis and devising better therapeutic and prevention strategies for COVID-19. Here we present within-host modelling of viral load dynamics observed in the upper respiratory tract (URT), drawing upon 2172 serial measurements from 605 subjects, collected from 17 different studies. We developed a mechanistic model to describe viral load dynamics and host response and contrast this with simpler mixed-effects regression analysis of peak viral load and its subsequent decline. We observed wide variation in URT viral load between individuals, over 5 orders of magnitude, at any given point in time since symptom onset. This variation was not explained by age, sex, or severity of illness, and these variables were not associated with the modelled early or late phases of immune-mediated control of viral load. We explored the application of the mechanistic model to identify measured immune responses associated with the control of the viral load. Neutralising antibodies correlated strongly with modelled immune-mediated control of viral load amongst subjects who produced neutralising antibodies. Our models can be used to identify host and viral factors which control URT viral load dynamics, informing future treatment and transmission blocking interventions.
    Keywords Medicine ; R
    Subject code 551
    Language English
    Publishing date 2022-01-01T00:00:00Z
    Publisher BMC
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  5. Article ; Online: Assessing the impact of imperfect adherence to artemether-lumefantrine on malaria treatment outcomes using within-host modelling

    Joseph D. Challenger / Katia Bruxvoort / Azra C. Ghani / Lucy C. Okell

    Nature Communications, Vol 8, Iss 1, Pp 1-

    2017  Volume 9

    Abstract: Artemether lumefantrine is widely used for the treatment of uncomplicated malaria. The impact of imperfect patient adherence to the six-dose regimen is hard to assess. Using adherence data for unsupervised patients, the authors model how suboptimal ... ...

    Abstract Artemether lumefantrine is widely used for the treatment of uncomplicated malaria. The impact of imperfect patient adherence to the six-dose regimen is hard to assess. Using adherence data for unsupervised patients, the authors model how suboptimal adherence affects treatment outcomes.
    Keywords Science ; Q
    Language English
    Publishing date 2017-11-01T00:00:00Z
    Publisher Nature Portfolio
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  6. Article ; Online: Assessing the impact of imperfect adherence to artemether-lumefantrine on malaria treatment outcomes using within-host modelling

    Joseph D. Challenger / Katia Bruxvoort / Azra C. Ghani / Lucy C. Okell

    Nature Communications, Vol 8, Iss 1, Pp 1-

    2017  Volume 9

    Abstract: Artemether lumefantrine is widely used for the treatment of uncomplicated malaria. The impact of imperfect patient adherence to the six-dose regimen is hard to assess. Using adherence data for unsupervised patients, the authors model how suboptimal ... ...

    Abstract Artemether lumefantrine is widely used for the treatment of uncomplicated malaria. The impact of imperfect patient adherence to the six-dose regimen is hard to assess. Using adherence data for unsupervised patients, the authors model how suboptimal adherence affects treatment outcomes.
    Keywords Science ; Q
    Language English
    Publishing date 2017-11-01T00:00:00Z
    Publisher Nature Publishing Group
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  7. Article ; Online: Modelling the benefits of long-acting or transmission-blocking drugs for reducing Plasmodium falciparum transmission by case management or by mass treatment

    Michael T. Bretscher / Jamie T. Griffin / Azra C. Ghani / Lucy C. Okell

    Malaria Journal, Vol 16, Iss 1, Pp 1-

    2017  Volume 12

    Abstract: Abstract Background Anti-malarial drugs are an important tool for malaria control and elimination. Alongside their direct benefit in the treatment of disease, drug use has a community-level effect, clearing the reservoir of infection and reducing onward ... ...

    Abstract Abstract Background Anti-malarial drugs are an important tool for malaria control and elimination. Alongside their direct benefit in the treatment of disease, drug use has a community-level effect, clearing the reservoir of infection and reducing onward transmission of the parasite. Different compounds potentially have different impacts on transmission—with some providing periods of prolonged chemoprophylaxis whilst others have greater transmission-blocking potential. The aim was to quantify the relative benefit of such properties for transmission reduction to inform target product profiles in the drug development process and choice of first-line anti-malarial treatment in different endemic settings. Methods A mathematical model of Plasmodium falciparum epidemiology was used to estimate the transmission reduction that can be achieved by using drugs of varying chemoprophylactic (protection for 3, 30 or 60 days) or transmission-blocking activity (blocking 79, 92 or 100% of total onward transmission). Simulations were conducted at low, medium or high transmission intensity (slide-prevalence in 2–10 year olds being 1, 10 or 40%, respectively), with drugs administered either via case management or mass drug administration (MDA). Results Transmission reductions depend strongly on deployment strategy, treatment coverage and endemicity level. Transmission-blocking was most effective at low endemicity, whereas chemoprophylaxis was most useful at high endemicity levels. Increasing the duration of protection as much as possible was beneficial. Increasing transmission-blocking activity from the level of ACT to a 100% transmission-blocking drug (close to the effect estimated for ACT combined with primaquine) produced moderate impact but was not as effective as increasing the duration of protection in medium-to-high transmission settings (slide prevalence 10–40%). Combining both good transmission-blocking activity (e.g. as achieved by ACT or ACT + primaquine) and a long duration of protection (30 days or more, such as ...
    Keywords Mathematical modelling ; Transmission ; Treatment ; Anti-malarial ; Mass drug administration ; Primaquine ; Arctic medicine. Tropical medicine ; RC955-962 ; Infectious and parasitic diseases ; RC109-216
    Subject code 535
    Language English
    Publishing date 2017-08-01T00:00:00Z
    Publisher BMC
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  8. Article ; Online: Projected health impact of post-discharge malaria chemoprevention among children with severe malarial anaemia in Africa

    Lucy C. Okell / Titus K. Kwambai / Aggrey Dhabangi / Carole Khairallah / Thandile Nkosi-Gondwe / Peter Winskill / Robert Opoka / Andria Mousa / Melf-Jakob Kühl / Tim C. D. Lucas / Joseph D. Challenger / Richard Idro / Daniel J. Weiss / Matthew Cairns / Feiko O. ter Kuile / Kamija Phiri / Bjarne Robberstad / Amani Thomas Mori

    Nature Communications, Vol 14, Iss 1, Pp 1-

    2023  Volume 10

    Abstract: Trial data have shown that post-discharge malaria chemoprevention (PDMC) reduces the risk of readmission and death in children previously hospitalised with severe malarial anaemia. Here, the authors use mathematical modelling to estimate the potential ... ...

    Abstract Trial data have shown that post-discharge malaria chemoprevention (PDMC) reduces the risk of readmission and death in children previously hospitalised with severe malarial anaemia. Here, the authors use mathematical modelling to estimate the potential epidemiological impacts of PDMC in malaria-endemic countries in Africa.
    Keywords Science ; Q
    Language English
    Publishing date 2023-01-01T00:00:00Z
    Publisher Nature Portfolio
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  9. Article: Mathematical Modelling to Guide Drug Development for Malaria Elimination

    Slater, Hannah C / Azra C. Ghani / Lucy C. Okell

    Trends in parasitology. 2017 Mar., v. 33, no. 3

    2017  

    Abstract: Mathematical models of the dynamics of a drug within the host are now frequently used to guide drug development. These generally focus on assessing the efficacy and duration of response to guide patient therapy. Increasingly, antimalarial drugs are used ... ...

    Abstract Mathematical models of the dynamics of a drug within the host are now frequently used to guide drug development. These generally focus on assessing the efficacy and duration of response to guide patient therapy. Increasingly, antimalarial drugs are used at the population level, to clear infections, provide chemoprevention, and to reduce onward transmission of infection. However, there is less clarity on the extent to which different drug properties are important for these different uses. In addition, the emergence of drug resistance poses new threats to longer-term use and highlights the need for rational drug development. Here, we argue that integrating within-host pharmacokinetic and pharmacodynamic (PK/PD) models with mathematical models for the population-level transmission of malaria is key to guiding optimal drug design to aid malaria elimination.
    Keywords antimalarials ; chemoprevention ; disease transmission ; drug resistance ; drugs ; malaria ; mathematical models ; patients ; pharmacokinetics ; therapeutics
    Language English
    Dates of publication 2017-03
    Size p. 175-184.
    Publishing place Elsevier Ltd
    Document type Article
    ZDB-ID 2036227-4
    ISSN 1471-5007 ; 1471-4922
    ISSN (online) 1471-5007
    ISSN 1471-4922
    DOI 10.1016/j.pt.2016.09.004
    Database NAL-Catalogue (AGRICOLA)

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  10. Article ; Online: Estimating the COVID-19 infection fatality ratio accounting for seroreversion using statistical modelling

    Nicholas F. Brazeau / Robert Verity / Sara Jenks / Han Fu / Charles Whittaker / Peter Winskill / Ilaria Dorigatti / Patrick G. T. Walker / Steven Riley / Ricardo P. Schnekenberg / Henrique Hoeltgebaum / Thomas A. Mellan / Swapnil Mishra / H. Juliette T. Unwin / Oliver J. Watson / Zulma M. Cucunubá / Marc Baguelin / Lilith Whittles / Samir Bhatt /
    Azra C. Ghani / Neil M. Ferguson / Lucy C. Okell

    Communications Medicine, Vol 2, Iss 1, Pp 1-

    2022  Volume 13

    Abstract: Brazeau et al. use a statistical modelling approach to estimate COVID-19 infection fatality ratios from seroprevalence data. The authors’ model accounts for seroreversion over the course of the pandemic, as well as other important uncertainties such as ... ...

    Abstract Brazeau et al. use a statistical modelling approach to estimate COVID-19 infection fatality ratios from seroprevalence data. The authors’ model accounts for seroreversion over the course of the pandemic, as well as other important uncertainties such as serologic test characteristics.
    Keywords Medicine ; R
    Language English
    Publishing date 2022-05-01T00:00:00Z
    Publisher Nature Portfolio
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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